Urea cycle disorder

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some covalent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. 

Urea cycle disorders (UCDs) Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCDs, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Precautions). 

Contraindications Active hepatic disease, urea cycle disorders... 

In the urea cycle, two molecules of ammonia combine with a molecule of carbon dioxide to produce a molecule of urea and water. The overall cycle involves a series of biochemical reactions dependent on enzymes and carrier molecules. During the urea cycle the amino acid ornithine (C5H12N202) is produced, so the urea cycle is also called the ornithine cycle. A number of urea cycle disorders exist. These are genetic disorders that result in deficiencies in enzymes needed in one of the steps in the urea cycle. When a urea cycle deficiency occurs, ammonia cannot be eliminated from the body and death ensues. 

The clinical syndrome of acute neonatal hyper-ammonemic encephalopathy described in the case report represents the classical presentation of a patient with a urea cycle disorder (UCD). It is important to note that this neonatal course represents only the most common and severe presentation of a UCD. This holds true for all the diseases listed in Table 18-1, with the exceptions of arginase (ARG-1) deficiency, which results in progressive spasticity of the lower limbs, and of the mitochondrial membrane transporters citrin and ornithine transporter 1 (ORNT-1). Deficiency of citrin results in adult-onset encephalopathy deficiency of... 

Long-Term Management of Patients with Urea Cycle Disorders... 

Brusilow SW Treatment of urea cycle disorders, in Desnick RJ (ed) Treatment of Genetic Diseases. Churchill Livingstone, New York, 1991, pp. 79-94. 

Brusilow SW, Maestri NE Urea cycle disorders diagnosis, pathophysiology and therapy. Adv Pediatr 43 127-170,1996. 

McCabe RB, Bachmann C, Batshaw, et al (eds) New developments in urea cycle disorders. Mol Genet Metab 81(suppl 1) S4-S91, 2004. 

Acute liver failure/metabolic crisis Galactosaemia Neonatal haemochromatosis Tyrosinaemia Urea cycle disorders Fatty acid oxidation defects... 

Evaluate for urea cycle disorders, as hyperammonemic encephalopathy, sometimes fatal, has been associated with valproate administration in these uncommon disorders urea cycle disorders, such as ormithine transcarbamylase deficiency, are associated with unexplained encephalopathy, mental retardation, elevated plasma ammonia, cyclical vomiting, and lethargy... 

Berry, G.T., Steiner, R.D. Long-term management of patients with urea cycle disorders. X Pediatr. 2001 138 56-60... 

Maestri NE, Hauser ER, Bartholomew D, Brusilow SW. Prospective treatment of urea cycle disorders. J Pediatr 1991 119 923-8. 

Summar ML. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001 138 S30-9. 

Whitington PF, Alonso EM, Boyle JT, Molleston JP, Rosenthal P, Emond JC, et al. Liver transplantation for the treatment of urea cycle disorders. J Inher MetabDis 1998 21 112-8. 

Burton B. Urea cycle disorders. Glin Liver Dis 2000 4 815-30, vi. 

Organic Acidurias Fatty Acid Oxidation Disorders Urea Cycle Disorders MSUD NKHG... 

Bachmann C, Colombo JP. Acid-base status and plasma glutamine in patients with hereditary urea cycle disorders. In Soeters PB, Wilson )HP, Meijer AJ, eds. Advances in ammonia metabolism and hepatic encephalopathy, 1st ed. Amsterdam Elsevier, 1988 72-8. 

Hyperammonemia resulting from any of the enzymatic disorders of the biosynthesis of urea, must be distinguished from other conditions in which plasma ammonia is raised, sometimes sufficiently so to cause clinical manifestation. Severe liver disease as a primary cause of acquired hyperammonemia may be excluded from consideration since it is readily distinguishable from urea cycle defects. However, there are a number of other conditions described with hyperammonia as a prime manifestation, which because they show some clinical and biochemical similarity to hereditary enzyme defects of the urea cycle, have been claimed to be urea cycle disorders. 

This condition has been described by Rett (RIO, Rll) and Rett and Stockl (R12) in 22 children, all girls, the oldest of them 13 years of age, from a survey of 6000 mentally subnormal children. In all 22, the blood ammonia was raised from 2 to 5 times the normal the highest being 165 /ig/100 ml. The blood urea was said to be normal in all cases, as was the plasma amino acids. Where liver biopsy was obtained, this was also normal. The brain was examined in 5 children who died. They showed cerebral atrophy but no Alzheimer Type II cells. A relationship between hyperammonemia and the cerebral changes of the syndrome was postulated and attention drawn to the similarity with some of the neurological manifestations of children with urea cycle defects. However, the cause of the hyperammonemia was unexplained, and it seems unlikely that these were examples of primary urea cycle disorders. 

J. G. Theone Treatment of urea cycle disorders. Journal of Pediatrics 134, 255 (1999). 

Traditional Chinese medicine draws heavily on animal products to the point at which it threatens the survival of tigers, rhinoceros and other large animals. It none the less has provided a number a leads for new drugs. Black bear bile is a particular source of active compounds. Tauroursodeoxycholic acid is already in use against human cholestatic disease, and 4-phenylbutyric acid has been approved for treatment of urea-cycle disorders. Other bile compounds could be used to treat type 2 diabetes, but all these materials, if they are to be widely used, require synthetic methods rather than the mass slaughter of black bears. 

A newborn becomes progressively lethargic after feeding and increases his respiratory rate. He becomes virtually comatose, responding only to painful stimuli, and exhibits mild respiratory alkalosis. Suspicion of a urea cycle disorder is aroused and evaluation of serum amino acid levels is initiated. In the presence of hyperammonemia, production of which of the following amino acids is always increased ... 

Oral sodium penylbutyrate has been used for years in young children with urea cycle disorders. At high doses, side effects include transient fluid retention, rashes, and unusual body odor. Increased HbF levels were seen in patients with SCA who received both high-dose (15 to 20 g/day) and low-dose (1 to 11 g/day) regimens. In the study of low-dose sodium penylbutyrate, increased HbF was seen within 5 weeks, but may not be sustained. The studies of butyrate involved a small number of patients. More clinical trials are needed to determine the optimal dosage and regimen. ... 

Persons who suffer from severe liver or kidney disease may be susceptible to ammonia intoxication, as it is chiefly by the actions of these organs that NH/ is biotransformed and excreted (Cordoba et al. 1998 Gilbert 1988 Jeffers et al 1988) individuals with hereditary urea cycle disorders are also at risk (Schubiger et al. 1991). In these individuals, the levels produced endogenously are sufficient to produce toxicity. Levels that are likely to be encountered in the environment, with the exception of those resulting from high-level accidental exposures, are insignificant, due to the low absorption rate, in comparison with levels produced within the body (WHO 1986). 

Urea cycle disorders Carbamylphosphate synthetase deficiency, ornithine transcarbamylase deficiency, and argininosuccinic acid synthetase deficiency Narcolepsy... 

When ornithine transcarbamoylase is deficient (urea cycle disorder), excess carbamoyl phosphate from the mitochondria leaks into the cytoplasm. The elevated levels of cytoplasmic carbamoyl phosphate lead to pyrimidine production, as the regulated step of the pathway, the reaction catalyzed by carbamoyl synthetase II, is being bypassed. Thus, orotic aciduria results. 

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